3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl esters

ABSTRACT

3-Hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl esters which, as intermediate products that can be industrially produced in a simple manner, can be used for the production of 2-methylpyridine-5-propionic acid alkyl ester.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to new 3-hydroxy-3-(2-methyl-5-pyridyl)-propionicacid alkyl esters, a process for the production of such compounds andthe use of such compounds for the production of2-methylpyridine-5-propionic acid alkyl esters.

2. Prior Art

2-Methylpyridine-5-propionic acid alkyl esters are importantintermediate products for a series of new histamine H₁ and H₂antagonists [Drugs of the Future, 7, 157 (1982)].

3-Pyridine propionic acid ethyl esters have been produced in a yield of92 percent by the hydrogenation of nicotinoyl acetate in the presence ofa palladium/barium sulfate catalyst [Graef et al., J. Org. Chem., 11,257, (1946)]. As the tests of the applicant herein prove, the reactioncannot be transferred to 6-methyl nicotinoyl acetate. Further, it isknown to produce 2-methylpyridine-5-alkyl propionic acid alkyl esterstarting from 6-methylpyridine-3-carbaldehyde by a three-stage synthesis(European Patent Application No. 0003677). But in such process, it isdisadvantageous that the starting product,6-methylpyridine-3-carbaldehyde, must be produced from2-methyl-5-vinylpyridine that is difficult to obtain and is veryexpensive.

BROAD DESCRIPTION OF THE INVENTION

The main object of the invention is to provide a simpler,industrially-and economically-feasible way to produce2-methylpyridine-5-alkyl propionates.

The main object of the invention is attained by the use of new3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl esters of theformula: ##STR1## wherein R is a lower alkyl group. Advantageously, thelower alkyl group is an alkyl group having 1 to 4 carbon atoms which canbe straight-chain or branched, but R is preferably a methyl or ethylgroup.

Production of the new invention compounds is achieved by starting from5-ethyl-2-methyl pyridine, which is converted to a 6-methyl alkylnicotinate by oxidation and esterification. Subsequently the 6-methylalkyl nicotinate is converted to 6-methyl nicotinoyl acetic acid alkylester with an alkyl acetate in the presence of an alkali metalalcoholate. Finally the 6-methyl nicotinoyl acetic acid alkyl ester ishydrogenated with hydrogen to 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl ester in the presence of a hydrogenationcatalyst.

Also according to the invention, the new3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl esters isacetylated with acetic anhydride to produce 2-methylpyridine-5-propionicacid alkyl ester. The respective acetylation intermediate product iseither isolated or directly hydrogenolyzed in situ in the presence of ahydrogenation catalyst with hydrogen to the final product.

The oxidation of 5-ethyl-2-methylpyridine to 6-methyl alkyl nicotinateis the object of Swiss Patent No. 654 577 and consequently is performedaccording to it.

The subsequent conversion to 6-methyl nicotinoyl acetic acid alkyl esteroccurs in the presence of an alkali metal alcoholate, advantageously inthe presence of sodium alcoholate, corresponding to the ester radical ofthe corresponding alkyl acetate under conditions known in the art forClaisen condensations. The 6-methyl nicotinoyl acetic acid alkyl estercan be isolated and purified, but preferably is used as a raw product inthe hydrogenation.

The hydrogenation preferably takes place in the presence of a usualhydrogenation catalyst. Preferably palladium on carbon is used in aconcentration of 1 to 10 percent of Pd on carbon, most preferably 5percent of Pd on carbon. Advantageously the hydrogenation is performedunder a pressure of 1 to 15 bars, preferably at 5 to 10 bars.

The lower aliphatic carboxylic acids, preferably acetic acid or thealiphatic alcohols corresponding to the ester radical, such as,methanol, ethanol, propanol or butanol, are advantageously used assolvents. But operation can also occur in aprotic solvents, e.g.,toluene.

Advantageously the hydrogenation is performed at a temperature in therange of 0° to 100° C., preferably at 50° to 80° C.

After the hydrogenation is completed, which lasts between 2 and 12 hoursdepending on the pressure, and after the usual work-up the3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl esters can beisolated in good purity.

Advantageously the alkyl esters have 1 to 4 carbon atoms.3-Hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester and3-hydroxy-3-(2-methyl-5-pyridyl)propionic acid ethyl ester areespecially preferred alkyl esters.

The new compounds form intermediate products for use in the productionof 2-methylpyridine-5-propionic acid alkyl esters. They either can beused directly as raw product from the preceding hydrogenation or can beespecially purified for the following acetylation step.

The acetylation takes place with acetic anhydride, advantageously in thepresence of a catalytic amount of a tertiary amine. Preferably4-dimethyl-aminopyridine is used as the catalyst in an amount of 0.0001mol to 0.01 mol in relation to 1 mol of3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid alkyl ester. The addedacetic anhydride itself can be used as a solvent, but usually, withregard to acetic anhydride, inert solvents such as methylene chloride,chloroform, carbon, tetrachloride, alkyl acetates such as ethyl acetateor even toluene are used.

The reaction temperature can vary over a range of 0° to 140° C., butadvantageously the operation is conducted at a temperature between 50°and 80° C.

The resulting acetylation product can be isolated and purified butpreferably it is further hydrogenolyzed in situ to the final product.

The hydrogenolysis takes place in the presence of a common hydrogenationcatalyst, advantageously palladium, which is applied to a carbon supportadvantageously in a concentration of 1 to 10 percent, with hydrogen. Thehydrogen pressure is advantageously chosen in a range of 1 to 15 bars,advantageously between 5 and 10 bars. The solvent usually corresponds tothe solvent from the acetylation step, but advantageously it isadditionally diluted with a lower organic carboxylic acid, e.g., aceticacid. The reaction temperature is advantageously between 0° and 100° C.,most advantageously between 50° and 80° C.

After hydrogenolysis is completed, the final product can be isolated inthe usual way, e.g., by subsequent neutralization and extraction. Anoptional purification can take place by means of high-vacuumdistillation. According to the invention process,2-methylpyridine-5-propionic acid alkyl esters with contents of greaterthan 97 percent and in yields of 50 to 60 percent, in relation to the6-methyl alkyl nicotinate, are obtained. Preferably,2-methylpyridine-5-propionic acid methyl ester and2-methylpyridine-5-propionic acid ethyl ester are produced correspondingto the particularly advantageous intermediate products, respectfully,3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester and ethylester.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, all parts, ratios, proportions and percentages are on aweight basis unless otherwise stated herein or obvious herefrom to oneordinarily skilled in the art.

EXAMPLE 1 Production of 2-methylpyridine-5-propionic acid ethyl ester1.1 6-methyl nicotinoyl acetic acid ethyl ester

35.8 g (0.52 mol) of sodium methylate and 200 ml of toluene were put ina 750-ml sulfonation flask. The reaction mixture was heated to refluxtemperature. A mixture of 55.7 g (0.33 mol) of 6-methyl nicotinic acidethyl ester (produced according to Swiss Patent No. 654 577) and 60.3 g(0.68 mol) of ethyl acetate was added drop by drop to the stirredsuspension over 7 hour period. The suspension was stirred at refluxtemperature for 22 hours and then cooled to 20° C. 200 ml of water and25 ml of concentrated hydrochloric acid were added and the phases wereseparated. The water phase was extracted with toluene and the combinedorganic phases were evaporated. Then the evaporation residue wasdistilled under vacuum. 25.9 g of 6-methyl nicotinoyl acetic acid ethylester, having a boiling point of 112°-130° C./0.2-0.4 mbar and a contentaccording to HPLC of 89.7 percent, was obtained (yield 33.6 percent, inrelation to the 6-methyl nicotinic acid ethyl ester).

1.2 3-hydroxy-3-(2-methyl-5-pyridyl) propionic acid ethyl ester

10.0 g (0.048 mol) of 6-methyl nicotinoyl acetic acid ethyl ester(distilled) was dissolved in 200 ml of 95 percent ethanol, mixed with 1g of 5 percent palladium on activated carbon and poured into a 1-literautoclave. The autoclave was put under 10 bars of hydrogen and stirredat 20°. The hydrogenation ended after 6 hours. The autoclave was opened,and the reaction solution filtered and evaporated. 10.0 g of3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester remained,which according to NMR and DC was pure. The yield, in relation to the6-methyl nicotinoyl acetic acid ethyl ester, was 100 percent.

A sample was distilled (b.p. 130° C./0.2 mbar, yield of the distillation94 percent, content according to GC 97 percent).

NMR (CDCl₃): δ 1.25 (t, J=7 Hz, 3 H);

2.50 (s, 3H)

2.70 (m, 2H)

4.15 (q, J=7 Hz, 2H)

4.50 (br, 1H)

5.15 (dd, J=11 and 5 Hz, 1H),

7.15 (d, J=10 Hz, 1H),

7.65 (dd, J=10 and 2 Hz, 1H),

8.35 (d, J=2 Hz, 1H).

IR (thin layer) cm⁻¹ 3200, 2980, 2920, 1730, 1600

1565, 1490, 1440, 1370, 1280,

1250, 1200, 1160, 1035, 875,

835, 740

MS 209 (M⁺, 8%): 194 (5), 122 (100), 94 (23).

1.3 2-methylpyridine-5-propionic acid ethyl ester

45.9 g (0.22 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acidethyl ester was dissolved in 100 ml of ethyl acetate, and 50 ml (0.53mol) of acetic anhydride and 0.1 g (0.82 mmol) of4-dimethylaminopyridine were added. The solution was stirred for 6 hoursat 20° C. and then evaporated. The residue was dissolved in 50 mlmethylene chloride and 50 ml of 5 percent sodium hydroxide solution, thephases were separated and the organic phase was evaporated. 55.8 g ofraw 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester wasobtained. This raw product was dissolved in 300 ml of acetic acid with3.0 g of 5 percent palladium on carbon and fed into a 1-liter autoclave.The autoclave was put under 8 bars of hydrogen and stirred at 70° C.Hydrogenation was ended after 6 hours. The autoclave was cooled andopened, and the solution was filtered and evaporated. The residue wasdissolved in 50 ml of water and brought to pH 8 by potassium carbonate.The solution was extracted three times with 100 ml of methylene chlorideand the organic extracts were evaporated. 42.5 g of raw 2-methyl-pyridine-5-propionic acid ethyl ester was obtained. The raw product wasdistilled (b.p. 100°-110° C./1.0 mbar). 22.0 g of2-methylpyridine-5-propionic acid ethyl ester was obtained, with a GCcontent of 92 percent. The yield, in relation to the 6-methyl nicotinoylpropionic acid ethyl ester, was 62.9 percent.

EXAMPLE 2 Production of 2-methylpyridine-5-methyl propionate 2.13-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester

61.1 g of raw 6-methyl nicotinoyl acetic acid methyl ester was producedfrom 51.3 g (0.33 mol) of 6-methy nicotinic acid methyl ester (producedaccording to the method of Swiss Patent No. 654 577), 45.9 g (0.82 mol)of sodium methylate and 49.6 g (0.67 mol) of methyl acetate according tothe general method of Example 1.1. 60.4 g of this raw product wasdissolved in 300 ml of acetic acid, 0.5 g of 5 percent palladium onactivated carbon was added, and the solution was poured into a 1-literautoclave. The hydrogenation was performed under a hydrogen pressure of8 bars and at a temperature of 65° C., and it lasted 3.5 hours. Theautoclave was cooled and opened, and the solution was filtered andevaporated. The residue was dissolved in 100 ml of water and 70 ml ofmethylene chloride, and adjusted to pH 7 with 52.8 g of 40 percentsodium hydroxide solution. The phases were separated, the water phasewas extracted twice, each with 70 ml of methylene chloride, and theorganic extracts were evaporated. 47.8 g of raw3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester wasproduced. 46.6 g of raw product was recrystallized from 45 ml oftoluene. The dried pure product had a content, as indicated by GC, of95.4 percent and a melting point of 74° to 76° C. The yield of 35.1 gcorresponded to 53.7 percent, in relation to the 6-methyl nicotinic acidmethyl ester used.

NMR (CDCl₃): δ 2.50 (s, 3H),

2.70 (m, 2H),

3.70 (s, 3H),

4.00 (br, 1H),

5.15 (dd, J=11 and 6 Hz, 1H),

7.10 (d, J=9 Hz, 1H),

7.65 (dd, J=9 and 2 Hz, 1H),

8.40 (d, J=2 Hz, 1H).

Ir (KBR) cm⁻¹ : 3460, 3140, 3040, 2970, 2840,

1735, 1605, 1495, 1440, 1395,

1355, 1325, 1280, 1230, 1205,

1165, 1075, 1030, 980, 930,

910, 890, 860, 740.

MS 195 (M⁺, 10%). 180 (5), 122 (100), 94 (32).

2.2 2-methylpyridine-5-methyl propionate

80.0 g (0.35 mol) of recrystallized3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester wasdissolved in 100 ml of toluene. 60.0 g (0.588 mol) of acetic anhydrideand 0.1 g (0.0009 mol) of 4-dimethyl-aminopyridine were added, and thesolution was stirred for 1 hour at 60° C. Then 20 ml of methanol wasadded. After 15 minutes, the solution was diluted with 250 ml of aceticacid, 1.5 g of 5 percent palladium on activated carbon was added, andthe solution was poured into the autoclave. The hydrogenation wasperformed under 8 bars of hydrogen at 65° C. for 5.5 hours. At the endof the hydrogenation, the autoclave was cooled, and the solution wasfiltered and evaporated. The evaporation residue was dissolved in 100 mlof water and 100 ml of methylene chloride and adjusted to pH 7 with 87.9g of 40 percent sodium hydroxide solution. The phases were separated,the aqueous phase was extracted with methylene chloride, and thecombined organic extracts were evaporated. 71.5 g of raw2-methylpyridine-5-propionic acid methyl ester was obtained. (Contentaccording to GC, 91.5 percent; yield, 92.1 percent in relation to the3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester used.) Theproduct was distilled to obtain a 97 percent product having with aboiling point of 100°-113° C./1-2 mbar. The yield of distilled productwas 88.5 percent, in relation to the3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester used.

EXAMPLE 3 2-methylpyridine-5-propionic acid methyl ester

48.0 g of raw 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methylester was produced according to the method of Example 2.1 from 51.3 g(0.33 mol) of 6-methyl nictonic acid methyl ester. This raw product wasnot recrystallized but was dissolved with 35.8 g of acetic anhydride and50 mg (0.41 mmol) of 4-dimethylaminopyridine in 50 ml of methylenechloride, and stirred at reflux temperature (40° C.) for 1.5 hours. 10ml of methanol was added, and the solution was evaporated after 0.5hours. The raw acetoxy compound was hydrogenated in 300 ml of aceticacid in the presence of 4 g of 5 percent palladium on activated carbon.The hydrogenation was conducted for 7 hours at a temperature of 50° C.and a hydrogen pressure of 5 bars. The 2-methylpyridine-5-propionic acidmethyl ester was isolated from the reaction mixture by evaporation andextraction as in Example 2.2. 39.1 g of raw 2-methylpyridine-5-propionicacid methyl ester was produced with a content of 83.1 percent accordingto GC, which corresponded to a total yield of 56.0 percent in relationto the 6-methyl nicotonic acid methyl ester.

EXAMPLE 4 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester

49.7 g of raw 6-methyl nicotinoyl methyl acetate was produced from 51.3g (0.33 mol) of 6-methyl nicotinic acid methyl ester, 37.3 g (0.67 mol)of sodium methylate and 49.6 g (0.67 mol) of methyl acetate according tothe general method of Example 1.1. 49.1 g of this product washydrogenated with 2.0 g of 5 percent palladium on activated carbon in300 ml of toluene. The hydrogenation took 7 hours at a pressure of 8bars of hydrogen and a temperature of 50° C. After hydrogenation, thesolution was filtered and evaporated. The raw product was recrystallizedfrom 40 ml of toluene. 21.0 g of3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester wasproduced with a content of 95.5 percent (according to GC). The yield was34.7 percent, in relation to the 6-methyl nicotinic acid methyl ester.

EXAMPLE 5 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid methyl ester10 g (0.05 mol) of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acidmethyl ester and 6.6 g (0.065 mol) of acetic anhydride were heated for 2hours to reflux temperature (140° C.) without solvent. The solution wascooled, poured into 50 ml of water and adjusted to pH 8 with 8 mol of 25percent ammonia solution. The product was isolated by extraction threetimes, each time with 50 ml of methylene chloride, and evaporation ofthe organic extracts. 11.2 g (92 percent) of the acetoxy compound wasobtained. EXAMPLE 6 3-Acetoxy-3-(2-methyl-5-pyridyl)-propionic acidethyl ester 4.3 g (0.021 mol) of3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester, 3.0 g (0.03mol) of acetic anhydride, 2.7 g (0.034 mol) of pyridine and 0.17 g(0.0017 mol) of 4-dimethylaminopyridine were stirred at 0° C. for 24hours. The solution was mixed with 25 ml of 5 percent sodium hydroxidesolution and extracted twice, each time with 25 ml of methylenechloride. The organic extracts were evaporated; the residue (4.7 g)contained 3-acetoxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester(yield 90.4 percent). EXAMPLE 7 Comparison test or example Hydrogenationof 6-methyl nicotinoyl ethyl acetate according to the method of Graef etal., J. Org. Chem., 11,257, (1946)

5 g (0.026 mol) of 6-methyl nicotinoyl ethyl acetate was dissolved in 40ml of acetic acid and 0.3 g of 5 percent palladium on barium sulfate,and then three drops of 60 percent perchloric acid were added. Thehydrogenation reaction was attempted under 1 bar of H₂ at 25° C., but noreaction was detected. 0.3 g of catalyst and three drops of perchloricacid were added, and the hydrogenation was continued at 80° C. under 1bar of H₂. After 4 hours the solution was filtered and evaporated. Theproduct was isolated by neutralization with aqueous potassium carbonateand extraction with chloroform. 5.3 g of raw product was obtained andpurified by column chromatography. Only traces of2-methylpyridine-5-propionic acid ethyl ester were obtained. The mainproduct (63 percent yield) was3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester.

What is claimed is:
 1. 3-Hydroxy-3-(2-methyl-5-pyridyl)-propionic acidalkyl ester having the formula: ##STR2## wherein R is a lower alkylgroup.
 2. 3-Hydroxy-3-(2-methy-5-pyridyl)-propionic acid methyl esterhaving the formula: ##STR3## 3.3-Hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester having theformula: ##STR4##